I-adamantyl carbonyl-3,3-diphenylpiperazines

ABSTRACT

The disclosure is directed to substituted 3,3diphenylpiperazines, substituted 3,3-diphenylpiperazin-2-ones and related compounds. The compounds are useful as sympathomimetic agents as evidenced by their production of mydriasis in standard laboratory animals.

United States Patent Freed et al.

[ Mar. 4, 1975 l-ADAMANTYL CARBONYL-3,3-DIPHENYLPIPERAZINES Inventors:Meier E. Freed, Paoli; Scott J.

Childress, Philadelphia, both of Pa.

Assignee: American Home Products Corporation, New York, NY.

Filed: Apr. 4, 1973 Appl. N0.: 347,940

Related US. Application Data Division of Ser. No. 161,322, July 9, 1971,Pat. No.

3,749,725, which is a division of Ser. No. 786,367,

Dec. 23, 1968, Pat. No. 3,631,047.

US. or ..260/268 PC, 260/247.2 A, 260/247.5 D, 260/268 R, 260/268 0,

260/268 PH, 260/268 TR, 260 268 PA,

2 0/26 r r1g2 0/268 H, 424/250 Int. Cl ..'.'...T.I Fwd 5 1772 Field ofSearch..... 260/268 MK, 268 R, 268 C, 260/268 TR, 268 PC, 268 PA [56]References Cited Primary Examiner-Donald G. Daus Assistant Examiner-JoseTovar Attorney, Agent, or Firm loseph Martin Weigman [5 7] ABSTRACT Thedisclosure is directed to substituted 3,3-diphenyl- Piperazines,substituted 3,3-diphenylpiperazin-Z-ones and related compounds. Thecompounds are useful as sympathomimetic agents as evidenced by theirproduction of mydriasis in standard laboratory animals.

2 Claims, No Drawings I I-ADAMANTYL CARBONYL-3,3 DIPHENYLPIPEKAZINESThis application is a division of our application Ser. No. 161,322 filedJuly 9, 1971 which issued on July 31,

2 alkyl, piperidino (lower) alkyl. and morpholino (lower) alkyl,hydrogen. lower alkano-yl, benzoyl and lower alkoxycarbonyl,

B is selected from the class consisting otoxo [O] and 97 8S N .7 ,725which was in turn a hydrogen [(H)2] with the proviso that when B is oxo,dtvtsionofour application 786,367 filed Dec. 23, 1968 A i ot hydrogelower alkanoyl, benzoyl and lower which issued on Dec. 28, 1971 as U.S.Pat. No. lk b l; a d R and R are the same or different'members selectedThis lnventlon re ate to a e Class Of plp r zm from the class consistingof hydrogen, halogen, lower compounds andto a method for theirpreparation. l0 lk 1 d b er alkoxy, More particularly, it relates tosubstituted As used herein the terms lower alkyl, lower alk- }P y PlP land Substitute}! oxy and the like describe groups containing from one -dp ny p p a -0n The COmPOUhdS Of s to about five carbon atoms, providedthat lower alkyl lhvehtloh y be represented y the formula groups containfrom two to about four carbon atoms A when they are part of thepyrrolidino (lower) alkyl,'pil peridino (lower) alkyl and morpholino(lower) alkyl groups.

Typical examples of the compounds of this invention arel-(2-phenethyl)-3,3-diphenylpiperazine and l-(3-dimethylaminopropyl)-3,3-diphenyl-Z-piperazinone.

The new and useful compounds ofthis invention may (I) be prepared by theprocess which is hereinafter schematica lly illustrated:

H H l 1 l 1 A r N R reduction alkylati n I bl 2 2 2 N R H l (II) (III)(IV) ac lation 0 all: lotion V '6 l 2 H (V) reduction H Where A isselected from the class consisting of lower alkyl, phenyl, halophenyl,trifluoromethylphenyl, lower alkylphenyl, lower alkoxyphenyl, phenoxy(lower) alkyl, halophenoxy (lower) alkyl, trifluoromethylphenoxy (lower)alkyl, lower alkylphenoxy (lower) alkyl, lower alkoxyphenoxy (lower)alkyl, hydroxy (lower) alkyl, omega-hydroxy-omega-phenyl (lower) alkyl,omega-amino (lower) alkyl, omega- (lower)alkylamino (lower) alkyl,omegadi(lower)alkylamino (lower) alkyl, pyrrolidino (lower) Where A, Rand R are as defined above, and R is lower alkyl or aryl.

Many of the starting compounds utilized in thepreparation of thecompounds of the present invention are known compounds which are,readily available from commercial sources, while others: can be easilyprepared in accordance with standard organic procedures well-known tothose skilled in the art.

Because the nitrogen containing compounds of the present invention arebasic, advantage may be taken of the water solubility of salts of thesecompounds formed with acids in the isolation and/or purification of theabove compounds for oral or parenteral administration. Of course, onlysalts formed with pharmacologically acceptable acids should be employedin therapeutic applications. Particularly effective salts are thoseformed with pharmacologically-acceptable acids having a pH value of 3 orlower. Such acids are wellknown in the art, for example: hydrochloric,hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, acetic, lactic,citric, tartaric, maleic, gluconic, fumaric, benzenesulfonic,toluenesulfonic, methanesulfonic, ethanesulfonic acids and the like.These salts may be prepared by procedures commonly employed in the art,for example, reacting the compound with an equivalent weight of theselected acid in aqueous solution and concentration of the solution.Other known procedures may also be employed.

The preparation of the l-substituted-3,3-diphenylpiperazine (IV) iscarried out in two steps by one of three alternate routes as shownabove. In one route 3,3-diphenylpiperazin-Z-one (II) is reacted with areducing agent, such as lithium aluminum hydride, diborane or the liketo form 2,2-diphenylpiperazine (III). The reaction may be carried out inan organic solvent medium such as ether, dioxane, tetrahydrofuran at atemperature range of about to 100C. for about 6 to 72 hours. Preferablythe reaction is carried out at a temperature range of about 30 to 70C.for about 12 to 36 hours.

The compound (III) may then be alkylated with an appropriate alkylatingagent such as an alkyl halide or an epoxide to add the desired alkylsubstituent and results in the l-substituted-3,3-diphenylpiperazine(IV).

The reaction is preferably carried out in an organic solvent medium at atemperature range of about 25 to 135C. for a period of about 1 to 18hours. Preferably the reaction is carried out at a temperature range ofabout 45 to 100C. for a period of about 6 to 12 hours. When the reactionis complete the products may be recovered and separated by well-knowntechniques. For instance, the reaction mixture may be filtered and thefilter cake washed with tetrahydrofuran, and then with methanol. Thefiltrates may be combined and concentrated under vacuum. The residue maybe redissolved in ether anddried over magnesium sulfate, filtered andconcentrated to obtain the product.

Alternately, the compound (III) is then acylated with an appropriateacylating agent, such as an acyl halide or haloformate, to produce theacylated 3,3-diphenylpiperazine (V). The latter compound (V) may then bereduced with an appropriate reducing agent such as lithium aluminumhydride, to form the l-substituted- 3,3-diphenylpiperazine (IV) productof the present invention. The reaction is preferably carried out in anorganic solvent medium at a temperature range of about 0 to 100C. for aperiod of about 6 to 72 hours. Preferably the reaction is carried out ata temperature range of about 30 to 70C. for a period of about 12 to 36hours.

When the reaction is complete the products may be recovered andseparated by well-known techniques.

Another route for the formation of l-substituted-3,3- diphenylpiperazine(IV) consists of alkylating a 3,3-diphenylpiperazin-2-one with a halogenderivative of the substituent desired to be added in the l-position in asuspension of sodium hydride or the like in an organic solvent medium,such as dimethylformamide or the like to form the l-substituted-3,3-

diphenylpiperazinone (VI). The reaction is preferably carried out at atemperature range of about 0 to 100C. for a period of about I to 24hours. Preferably the reaction is carried out at a temperature range ofabout 30 to C. for a period of about 6 to I2 hours. The latter is thenreduced with an appropriate reducing agent such as lithium aluminumhydride as described above, to form thel-substituted-3,3-diphenylpiperazine (IV) product of the presentinvention. When the reaction is complete the products may be recoveredand separated by well-known techniques.

The I-substituted-3,3-diphenylpiperazine (IV) andl-substituted-3,3-diphenyl-2-piperazinone (VI) of the present inventionhave utility in experimental pharmacology. The compounds aresympathomimetic agents which is particularly evidenced by theirproduction of mydriasis in a host.

In the pharmacological evaluation of the compounds as mydriatic agentsthe in vivo effects are tested as follows. The compound to be tested isadministered intraperitoneally to three mice (14 to 24 grams) at each ofthe following doses: 400, I27, 40 and 12.7 milligrams per kilogram ofhost body weight (mg/kg). The animals are watched for a minimum of twohours during which time signs of general stimulation (that is, increasedspontaneous motor activity, hyperactivity of tactile stimulation,twitching), general depression (that is, decreased spontaneous motoractivity, decreased respiration) and autonomic activity (that is miosis,mydriasis, diarrhea) are noted. W

The compounds of the present invention in the above test procedure wereshown to be mydriatic agents at dosages of 4, 12.7, I27 and 400milligrams per kilogram of the body weight of the host (mg./kg.).

When the compounds of this invention are employed as described above,they may be administered alone or in combination with pharmacologicallyacceptable carriers, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmacological practice. For example, theymay be administered orally in the form of tablets or capsules containingsuch excipients as starch, milk, sugar, certain types of clay and soforth. They may be administered sublingually in the form of troches orlozenges in which the active ingredient is mixed with sugar and cornsyrups, and then dehydrated sufficiently to make is suitable forpressing into a solid form. They may be administered orally in the formof solutions which may contain coloring and flavoring agents or they maybe injected parenterally, that is intramuscularly, intravenously orsubcutaneously. For parenteral administration they may be used in theform of a sterile solution containing other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular subject under treatment. Generally, treatmentis initiated with small dosages substantially less than the optimum doseof the compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally be found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame effect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects.

In order more clearly to disclose the nature of the present invention.specific examples of the practice of the invention are hereinaftergiven. It should be under- 5 EXAMPLE 1 The following example illustratesthe preparation of 2,2-diphenylpiperazine dihydrochloride, a compound offormula Ill.

The reaction may be illustrated:

ia t 5 To a stirred suspension of lithium ait'trhintihfiydfiti (84.4grams, 2.22 mole) in dry tetrahydrofuran (2liters), in a 5 liter3-necked flask fitted with a seal-type stirrer, dropping funnel andcondenser fitted with a calcium chloride filled drying tube, was added,in portions, 3,3-diphenylpiperazine-2-one (140, grams, 0.555 mole). Thereaction was heated at reflux for 3 hours, stirred overnight at roomtemperature, and then refluxed again for 6 hours and cooled in anice-bath. The reaction mixture was decomposed by the cautious additionof water (255 milliliters) and stirred 3 hours at room temperature. Theinorganic material was filtered off and the filter-cake washed withtetrahydrofuran, then with methanol. Combined filtrates wereconcentrated under reduced pressure. The residue was taken up inanhydrous ether (1.500 ml.), filtered clear and again concentrated.Residue solidified after standing several days. The yield was 121.9grams equal to 92.1 percent of theoretical yield. Treatment of an ethersolution of 2,2-diphenylpiperazine with dry hydrogen chloride gave awhite dihydrochloride which was filtered off, washed with ether, driedand recrystallized from methanol-isopropanol. The melting point of theproduct was 292-294C.

Based on the formula CmHgnNgClg, it was calculated that the elementalanalysis by weight would be 61.72 percent carbon, 6.47 percent hydrogen,8.99 percent nitrogen and 22.78 percent chlorine. The product wasanalysed and the content was found to be 61.71 percent carbon, 6.26percent hydrogen, 9.05 percent nitrogen. and 22.70 percent chlorine. Theforegoing may be expressed:

Analysis calculated for cu HgqNzclgi C, 61.72; H,

6.47; N, 8.99; Cl, 22.78.

Found: C. 61.71; H, 6.26: N, 9.05; Cl, 22.70.

In the pharmacological evaluation described above, the product was foundto be a mydriatic agent at 4 mg./kg. administered orally, The highestnon-lethal dose administered was 127 mg./kg.

EXAMPLES 2-27 Following the procedure of Example l by substitutingappropriate reactants for 3,3-diphenylpiperazin- 2-one, the followingsubstituents of R and R are added when B is (H)- and A is hydrogenresulting in compounds of Formula lll.

Example The following example illustrates the preparation ofl-ethoxycarbonyl-3,3-diphenylpiperazine, a compound of formula V andl-methyl-3,3-diphenylpiperazine. hydrochloride, a compound of formulaIV.

The reaction may be illustrated:

ii (HG-002325 A solution of 2,2-diphenylpipera2ine (15.7 grams, 0.0242mole), triethylamine (5.4grams, 0.0532 mole) and ether ml.) was cooledto 3C. A solution of ethyl chloroformate (5.78 grams, 0.0532 mole) inether (50 ml.) was added at 3-9C. over a period of A hour. The mixturewas stirred in the icebath for 1 hours, then at room temperature for 5hours. The solid was filtered off to give 4.34 grams of triethylaminehydrochloride. The filtrate was concentrated under vacuum. The residuewas dissolved in ether (200 ml.) and treated with saturated ethanolichydrogen chloride to pH 1. The hydrochloride of the product, I-ethoxycarbonyl-3,3-diphenylpiperazine, separated as an oil from theether. On standing this oil solidified. It was filtered off, washed withether, and dried. The yield was 6.65 grams having a melting point of228-23 1C., being equivalent to a 79.3 percent yield.

The hydrochloride was converted back to base by suspending it in 75 ml.water and adding 50 percent aqueous sodium hydroxide to raise the pH to12. A solid formed which was extracted into ether, washed with saline,dried over magnesium sulfate and filtered clear. This filtrate wasconcentrated under vacuum. The residue (4.6 grams) was dissolved in drytetrahydrofuran (75 ml.) and added to a stirred suspension of lithiumaluminum hydride (0.86 grams, 0.0225 mole) in 50 ml. of tetrahydrofuran,refluxed 28 hours and cooled. Water (4 ml.) was added slowly, stirredseveral hours, and filtered. The filtercake was washed first withtetrahydrofuran and then with methanol. The filtrates were combined andconcentrated under reduced pressures. The residue was redissolved inether (250 ml.) and dried over magnesium sulfate, filtered and againconcentrated. The residue, 21 yellow oil (4.9 grams) was dissolved in 30ml. ethanol.

The clear solution was treated with ethanolic hydrogen chloride (pH=land diluted to 500 ml. with ether. After standing in the cold'(5C.) asolid formed and was filtered off, washed and dried. The product wasrecrystallized from methanolacetone and afforded 2.4 grams (56.8 percentof theoretical yield) of white crystals of1-methyl-3,3-dlphenylpiperazine monohydrochloride, having a meltingpoint of 244245C.

Analysis calculated for C H CIN C, 70.70; H,

7.32; CI, 12.27; N, 9.70.

Found: C, 70.64; H, 7.23; CI, 11.98; N, 9.47.

In the pharmacological evaluation described above, the product was foundto be a mydriatic agent at 12.7 mg./kg. administered orally. The highestnon-lethal dose administered was 127 mg./kg.

EXAMPLE 28A The following illustrates the preparation of l-Acetlyl-3,3-diphenylpiperazine, a compound of formula IV.

To a solution of 2,2-diphenylpiperazine (5.7 g., 0.0242 mole) andtriethylamine (2.70 g., 0.0266 mole) in ether (200 ml.) at C is added,slowly and with stirring and cooling, a solution of acetyl chloride(1.95 g., 0.025 mole) in 50 ml. of ether. Following addition, thereaction mixture is stirred for 1 hour. The solid material(triethylamine hydrochloride) is filtered off and well washed withether. The solvent is removed from the combined filtrate and washingsunder reduced pressure, leaving a solid residue of product.

EXAMPLE 28B The following illustrates the preparation of l-Ethyl-3,3-diphenylpiperazine, a compound of formula IV.

To a stirred suspension of lithium aluminum hydride (3.8 g., 0.1 mole)in 250 ml. of dry tetrahydrofuran is added slowly a solution ofl-acetyl-3,3-diphenylpiperazine (9.5 g., 0.025 mole) in 150 ml.oftetrahydrofuran.

After the addition is completed the reaction mixture is stirred andrefluxed 8 hours. After cooling, water (14 ml.) is added slowly and withstirring and cooling. After complete addition the reaction mixture isallowed to stir at room temperature for 2 hours, then filtered. Thefilter cake is washed well with tetrahydrofuran, then with isopropanol.Solvent is removed from the combined filtrate under reduced pressure.The residue is taken up in ether and treated with dry hydrogen chloride.The precipitated hydrochloride is then filtered off. washed with etherand recrystallized.

EXAMPLE 28C The following illustrates the preparation of (2-methylpropionyl)-3,3-diphenylpiperazine, a compound of formula IV.

In the manner of example 28A, a solution of 2,2-diphenylpiperazine (5.7g., 0.0242 mole) and triethylamine (2.7 g., 0.0266) in ether istreatedwith an ethereal solution of (2-methyl)propionyl chloride to givethe desired product.

EXAMPIZE 28D EXAMPLES 29-54 Following the procedures of Example 28A andExample 288 but substituting appropriate compounds for2,2-diphenylpiperazine, acetyl chloride, and l-acetyl-3,3-diphenylpiperazine, the following substituents of R R, and A may beadded where B is (H) Example R1 R2 A 29 Cl H c H, 30 F H (2 H, 31 Br HC,H,, 32 I H C a 33 Cl Cl C2H,-, 34 F C1 C,H 35 Br Cl C,H,, 36 1 F C,,H37 CH H (CH;,)2CHCH2 38 C. ,H,-, H H;, 39 CH; H (2H5 40 (,H, H C,H,I 41CH3 CH3 (3H, 42 C H -,O (2 H, CH .CHCH 43 CH CH3 CH 44 on, can can 45CH;,() H (3H,- 46 11,0 H C,,H 47 C rr-0 H C,H,. 48 C,H,.0 H (CH=,)2CHCH249 CHBO CH;.O CH 50 C2H,-,O (EH50 CQH; 51 C;,H;O C2H -,O C H; 52 C,H,,0CH O C,H,, 53 Cl CH3 CQHT 54 C2H,-, CHHO (CH3)2CHCH2 EXAMPLE 55 Thefollowing example illustrates the preparation ofl-(2-phenethyI-3,3-diphenylprperazme, a compound of formula IV.

The reaction may be illustrated:

A mixture of 2,2-dipheny1piperazine (5.0 grams, 0.021 mole),phenethylbromide (3.89 grams, 0.021 mole), triethylamine (2.13 grams,0.021 mole) and toluene (75 ml.) was stirred at reflux for 24 hours. Themixture was cooled and the triethylamine hydrobromide (2.76 grams,having a melting point of 245247C.) was filtered off. The filtrate wasconcentrated. The residue was recrystallized from aqueous ethanol togive 4.80 grams of product 1-(2-phenethyl)- 3,3-diphenylpiperazine (66.7percent of theoretical yield), having a melting point of 8889.5C.

Analysis calculated for C H N C, 84.17; H, 7.65;

N, 8.18. Found: C, 84.35; H, 7.81; N, 8.11.

EXAMPLE 56 Following the procedure used in Example 55,2,2-diphenylpiperazine is mixed with cinnamyl bro mide and heated in aninert solvent for -24 hours to obtain 1-cinnamyl-3,3-diphenylpiperazine.

EXAMPLE 57 Following the procedure used in Example 55,2,2-diphenylpiperazine is mixed with an equivalent amount ofmorpholinoethyl chloride and heated in an inert solvent for 2024 hoursto obtain 1- (morpholinoethyl)-3,3-diphenylpiperazine.

EXAMPLE 58 The following example illustrates the preparation of3,3-Diphenyl-l-piperazineethanol, a compound of formula IV.

To a stirred mixture of 2,2-diphenylpiperazine (5.0 g, 0.021 mole),powdered potassium carbonate (4.15 g., 0.03 mole) and benzene (60 ml) at45C, was added a solution of 2-bromoethanol (2.63 g., 0.021 mole) in 4hour. The mixture was stirred at reflux for 3% hours after the additionhad been completed, then it was cooled and filtered. The filtrate wasfreed of solvent to give the crude product.

A sample of the product was converted to the fumarate by adding 3.888 g.(0.01376 mole) in acetone (50 ml.) to a solution of 0.793g. (0.00688mole) fumaric acid in acetone (100 ml.). The salt that separated oncooling was recrystallized twice from methanolacetone to give thefumarate. 2.13 g. melting at l72-175C.

Analysis for C H N O calculated F/(Z C, 70.56; H,

7.11; N, 8.23 Found 71: C, 70,29; H, 7,24; N, 7.96.

EXAMPLE 59 Following the procedure used in Example 58, 3- bromopropanolis substituted for 2-bromoethanol to obtain 3,3-diphenyll-piperazinepropanol.

EXA MPLES 60 76 Following the procedure used in Example but substitutingappropriate compounds for 2,2-diphenylpiperazine and phenethylbromidethe following substituents for R, R and A may be added when B ishydrogen:

of formula IV.

The reaction may be illustrated:

ll 12 A mixture of 2,2-diphenylpiperazine (5.0 grams, A mixture of2,2-diphenylpiperazine (2.5 grams, 0.021 mole), ,B-bromophenetole (4.23grams, 0.021 0.0105 mole), 3-dimethylaminopropylchloride hydromole),triethylamine (2.13 grams. 0.021 mole) and tolchloride (1.66 grams,0.0105 mole), and triethylamine uene (75 ml.) was stirred at reflux for24 hours. The (2.34 grams, 0.0231 mole) and dimethylformamide mixturewas cooled and the triethylamine hydrobro- 5 (20 ml.) was stirred at70C. for 4% hours. The mixture mide (3.37 grams, having a melting pointof was poured into ice water (75 ml.). It was extracted 245-248C.) wasfiltered off. The filtrate was concenwith ether (175 ml. in 3 portions).The combined extrated. The residue was recrystallized from aqueoustracts were washed with saturated sodium chloride soethanol to give 3.65grams of product, l-phenoxyethyllution, dried over anhydrous magnesiumsulfate and 3,3-diphenylpiperazine (a 48.5 percent of theoretical lconcentrated to give a residual oil (2.5 grams). yield), having amelting point of 95-97.5C. The fumarate was prepared by adding 2.324grams Analysis calculated for CHI-126N201 C, 80.41; H, 7.31; (0.00719mole) of the base in acetone (50 ml.) to a hot solution of fumaric acid(1.252 grams, 0.01078 mole) FOUHdI 7-67. in acetone (150 ml.). The solidthat was obtained on In the pharmacological evaluation described above,li w filt red off, washed and dried to give 2.59 the product was foundto be a mydriatic agent at 12.7 grams of solid1-(3-dimethylaminopr0pyl)-3,3- g-/ gadministered parentefally- Thehighest dose diphenylpiperazine, a 53.4 percent of theoretical yield,administered was 400 mg./kg. and was non'lethal. h i a lti i t f 165 5168 5C EXAMPLES 78 86 AgaggsisNczgltluslated for C H N O C, 65.17; H,Following the procedure ofExample 77 but substitut- I F d; C, 64,69; H,6 99; N, 8,44, pp p Compounds for ziz'diphenylpipemllne Inpharmacological evaluation described above, the and B-bromophenetole thefollowing substituents for d t wa f und to be a mydriatic agent at 400R. R and A may be added when B is hydrogen: jk d i i d all EXAMPLE 88Example R1 R2 A 5 The following example illustrates the preparation of(8 C2115 H pOCHgOHgOHg 1-(3-dimethylaminopropyl)-3,3-diphenylpiperazine,a 79 H 0(3HCH2 compound of formula IV. (See Example 93). I

0H3 The reaction may be illustrated:

' ({H CH CH N(CH ?H CH CH N(GH IlZilJXlI-I tetramrdrofuran 5 ggg ggg ggTo a suspension of lithium aluminu m hydride 3.3 0H. 11001120112 4Sgrams, 0.1 mole) in dry tetrahydrofuran (100 ml.) 15 g i added, slowly,and with stirring, a solution of l-(3- H O(CH1)@CH1dimethylaminopropyl)-3,3-diphenyl-2-piperazinone H woHzcHwfl'om) (8.4grams, 0.025 mole) in dry tetrahydrofuran. After addition is completethe reaction is stirred and refluxed 18 hours, then cooled. The reactionmixture is decom- EXAMPLE 87 posed by the slow addition of water (12-14m1), fol- The following example illustrates the preparation of lowed bystirring for two hours. The inorganic material1-(3-dimethylaminopropyl)-3,3-diphenylpiperazine, a is filtered from thesolution and washed with tetrahycompound of formula IV. drofuran andisopropyl alcohol. The solvent is removed The reaction may beillustrated: is by evaporation at reduced pressure, and the residue is(31 03 CH2N(CH3)2 toluene then taken into ether, filtered clear, andtreated carefully with dry hydrogen chloride. The product, l-(3-dimethylaminopropyl)-3,3-diphenypiperazine hydrochloride is purified byrecrystallization from pentaneacetone.

EXAMPLE 89 The following example illustrates the preparation of1-(3-dimethylaminopropyl)-3,3-diphenylpiperazine, a compound of formulaIV.

A mixture of 2,2-diphenylpiperazine (5.0 grams, 0.021 mole),3-dimethylaminopropylchloride hydrochloride (3.32 grams, 0.021 mole),triethylamine (4.26 grams, 0.042 mole) and toluene (75 ml.) was stirredat reflux for 26 /2 hours. The mixture was cooled, then filtered toremove the triethylamine hydrochloride formed. The filtrate wasconcentrated to dryness. The residue was dissolved in ether and filteredwith the aid ofSuper-Cel. Addition of anhydrous hydrogen chloridefollowed by filtration gave 7.48 g. hyrdrochloride. Recrystallizationfrom methanol-acetone gave 1.68 grams unreacted 2,2-diphenylpiperazinehydrochloride. The mother liquor was concentrated and the residue wasrecrystallized from isopropanol to give the product hydrochloride, 2.44grams decomposing at about 130C. This was converted to the base bytreating its aqueous solution with potassium carbonate to pH andextracting three times with ether. The etheral extracts were combined,washed with saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate and freed of solvent to give the product asan oil, 1.4 grams.

The base was converted to the fumarate by adding 1.240 grams, (0.00383mole) in acetone ml.) to a boiling solution of fumaric acid (0.668grams, 0.00575 mole) in acetone (100 ml.). The solution was concentratedto a volume of 100 ml. The solid which precipitated on chilling wasrecrystallized from methanolacetone to give the fumarate, 1.40 grams,melting at 165166.5C.

Analysis calculated for C H N O C, 65.17; H,

7.09; N, 8.45. u oer-rare. ,9 N 8- EXAMPLE 90 The following exampleillustrates the preparation of lallyl-3,3-diphenylpiperazine, a compoundof formula IV A mixture of 2,2-diphenylpiperazine (5.0 grams,

The base was converted to the fumarate by adding a solution of 6.19grams to a boiling solution of fumaric acid (2.58 grams) in acetone (300ml.). The resulting solution was freed of solvent and the residuerecrystallized twice from ethyl acetate to give the fumarate, 5.00grams, melting at l74-l75C.

Analysis calculated for C H N O C. 70.03; H.

Found: C, 70.04; H, 6.41; N. 6.99.

In the pharmacological evaluation described above, the product was foundto be a mydriatic agent at 127 mg./kg. administered orally. The highestdose administered was 400 mg./kg. and was non-lethal.

EXAMPLE 9] The following example illustrates the preparation ofl-adamantoyl-3,3-diphenylpiperazine. a compound of formula IV.

To a solution of 2,2-diphenylpiperazine (5.00 grams, 0.021 mole) andtriethylamine (2.13 grams. 0.021 mole) in acetone (20 ml.) was added asolution of ladamantanecarboxylic acid chloride (4.18 grams,

0.021 mole) in acetone (30 ml.) over a period of /a hour. The mixturewas stirred at reflux for 4 hours,

then cooled. The solid was filtered off, washed and melting at 182 184C.

Analysis calculated foi'cg'a n o; C, 80.96; 1 118.05;

Found: C, 81.20; H, 8.18; N, 7.12.

EXAMPLE 92 The following example illustrates the preparation ofa,3,3-triphenyl-l-piperazineethanol, a compound of formula IV.

A solution of 2,2-diphenylpiperazine (5.0 grams, 0.021 mole) in benzene(20 ml.) was heated to C. A solution of styrene oxide (2.5.3 grams,0.021 mole) in benzene was added at 60C.-over a period of A hour. Thesolution was stirred at reflux for 3 hours, then cooled and freed ofsolvent. The residue was recrystallized from ether-pentane to give theproduct, 2.88 grams (38.3 percent yield) melting at l20l2lC.

Analysis calculated for C H N O: C. 80.41; H, 7.31;

N, 7.82. Found: C, 80.16; H, 7.42; N, 7.73.

EXAMPLE 93 The following example illustrates the preparation ofl-(3-dimethylaminopropyl)-3,3-diphenyl2- piperazinone, a compound offormula VI.

The reaction may be illustrated:

., 3 CH2QH2CH2N\ To a suspension of sodium hydride (0.88 grams, 0.02mole of a 55 percent by weight dispersion in mineral oil) anddimethylformamide 10 ml.) wasadded a solution of3,3-diphenyl-2-piperazinone (5.05 grams, 0.02 mole) in dimethylformamide (45 ml.) over a period of A hour. The mixture was stirred atroom temperature for 1% hours after completion of the addition. Asolution of freshly distilled 3-dimethylaminopropylchloride (2.44 grams,0.02 mole) in dimethylformamide (20 ml.) was added over a period of Ahour. The mixture was stirred at room temperature for 23 hoursfthe npoured into water (150 ml.). The mixture was acidified to pH 1 withconcentrated hydrochloric acid. After extraction with petroleum ether (3portions, 50 ml. each), it was basified to pH 12 with 50 percent aqueoussodium hydroxide. The resulting mixture was extracted EXAMPLE 106 amideml.) was added in 10 minutes. The mixture with ether (3 portions, 100ml. each). The combined extracts were dried over magnesium sulfate,filtered and concentrated. The residue was dissolved in boilingacetone-cyclohexane (300 ml.). The solution was con-- centrated to halfvolume. The solid that was formed on chilling was recovered to give 1.84grams unreacted 3,3-diphenyl-2-piperazinone. The mother liquor wasconcentrated to a volume of 10 ml. The solid that was formed on chillingwas filtered off and recrystallized twice from cyclohexane to give 1.12grams of product 1-(3-dimethylaminopropyl)-3,3-diphenyl-2- piperazinone,having a melting point of 78-8lC., (a:

16.6 percent of theoretical yield).

Analysis calculated for C H N O: C, 74.74; H, 8.07; 30

N, 12.45. Found: C, 74.97; H, 8.07; N, 12.32. In the pharmacologicalevaluation described above, the product was found to be a mydriaticagent at 400 mg./kg. administered orally.

EXAMPLES 94-105 Following the procedure of Example 93 but substitutingappropriate starting materials for 3,3-diphenyl-2- piperazinone and3-dimethylaminopropylchloride, the following substituents of R, R and Amay be obtained when B is oxo. As used below C,H,,N is pyrrolidino, C HN is piperidino and C,H,,NO is morpholino.

Example was stirred at 50C. for 24 hours. It was cooled, then pouredinto water (200 ml.) and acidified to pH 1 with concentratedhydrochloric acid. It was extracted three times with light petroleumether. The aqueous phase was basified to pH 12 with 50 percent sodiumhydroxide and then extracted three times with ether. The combinedetheral extracts were washed with saturated aqueous sodium chloridesolution, dried over anhydrous sulfate and freed of solvent. The residuewas recrystallized twice from acetonecyclohexane and once frombenzene-pentane to give the product, 1.55 grams (29.1 percent yield)melting at l50-l53C.

Analysis calculated for C H N oz C, 76.66; H, 6.81;

Found: C, 76.44; H, 6.74; N, 10.72.

In the pharmacological evaluation described above, the product was foundto be a mydriatic agent at 127 mg./kg. administered orally. The highestdose adminis- {tered was 400 mg./kg. and was non-lethal.

What is claimed is:

1. A compound having the formula:

A l N Where A is adamantylcarbonyl; and R and R are the same ordifferent members selected from the class consisting of hydrogen,halogen, lower alkyl and lower alkoxy.

2. A compound as defined in claim 1 which is:latlamantylcarbonyl-3,3-diphenylpiperazine.

1. A COMPOUND HAVING THE FORMULA:
 2. A compound as defined in claim 1which is: 1-adamantylcarbonyl-3,3-diphenylpiperazine.